2-Imino-piperidines

ABSTRACT

The compounds are of the class of 2-imino-methyleneimines which are useful for their antiinflammatory and ganglionic blocking activities, and their effect on blood pressure and heart rate.

United States Patent P005 June 3, 1975 [5 Z-IMINO-PIPERIDINES [51] Int.Cl C07d 29/28 [58] Field of Search 260/293.78, 293.58; [75] Inventor.George Ireland Poos, Ambler, Pa. 85/734; 738/379; 649/812; 409/563 [73]Assignee: McNeil Laboratories, Incorporated.

or WaShiflgwn, P4 [56] References Cited [22] Filed: July 13, 1973 UNITEDSTATES PATENTS 1 pp NO: 379030 3,531,487 9/1970 Berger et al. i.260/293.78

Related US. Application Data Primary Examiner-Norma S. Milestone [60]Continuation-impart of Ser. NO. 85,734, on. 30, AssisramExaminer-Sinters 1970, abandoned, which is a division of Ser. No. 738,379, Junel7, 1968, abandoned. which is a [57] ABSTRACT continuation-in-part ofSer. No. 649,812, June 29, The Compounds are of the class of 1967,abandoned. which is a continuation-in-part of f 1 f Ser. No 409563 6 964abandoned methyleneimines which are use u ortiieir antnnflammatory andganglionic blocking activities, and their 52 us. c1... 260/293.78;260/239 B; 260/239 BE; effect blood Pressure and hear 260/293 5l:260/293.58; 260/293.72; 260/293.73; 260/293.83; 260/293.85; 260/2939;260/3265 A; 260/3265 D; 260/3265 L: 260/3268; 260/326.84; 260/326.85;260/326.87; 424/244; 424/267; 424/274 3 Claims, No Drawings 1Z-IMINO-PIPERIDINES CROSS-REFERENCE TO RELATED APPLICATIONS This is acontinuation-in-part application of my copending application Ser. No.85,734, filed Oct. 30, 1970 now abandoned, which in turn is a divisionalapplication of application Ser. No. 738,379, filed June 17, 1968, nowabandoned, which in turn is a continuationin-part application ofapplication Ser. No. 649,812, filed June 29, 1967, now abandoned, whichin turn is a continuation-in-part of application Ser. No. 409,563, filedNov. 6, 1964, now abandoned.

DESCRIPTION OF THE INVENTION This invention relates to new chemicalcompounds and the preparation thereof. More particularly, this inventionrelates to novel l-(lower alkyl)-2-aralkyliminopyrrolidines of theformula:

lower alkyl and l-R -2-aralkylimino-methyleneimines of the formula:

in which Alk represents a member selected from the group consisting ofdill-CH- and a saturated straight or branched chain alkylene having I to3 carbon atoms, R represents a member selected from the group consistingof phenyl and substituted phenyl, R is a member selected from the groupconsisting of lower alkyl and benzyl, and n is a whole integer from 3 to5. The therapeutically active nontoxic acid addition salts of theforegoing compounds are also embraced within the scope of thisinvention.

As used herein, lower alkyl" may be straight or branch chained and havefrom I to 7 carbon atoms, such as, for example, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl and the like; andsubstituted phenyl means a phenyl having one or more substituentsattached to it, such as, for example, lower alkyl, lower alkoxy,hydroxy, halo, methylenedioxy and the like, the preferred substituentsbeing lower alkyl, lower alkoxy and halo, more preferably, chloro. Whenmore than one substituent is present on said phenyl, they may be thesame or different.

The novel compounds of this invention have several usefulpharmacological properties which make them suitable for pharmaceuticalapplications. For example, the compounds of formula (l-a) possessantiinflammatory activity, as exemplified by l-methyl-2-[(l,l-diphenylmethyl)imino]-pyrrolidine, which has been observed toproduce about a 66% inhibition in the standard kaolin-induced rat pawedema assay after a mg/kg oral dose. In addition, the compounds offormula (la) possess central nervous system depressant activity. Withthe compounds of formula (Ib), wherein R is hydroxy-substituted phenyl,hypotensive and cardiac stimulating activity in anesthetized dogs isobserved at doses of about 10 mg/kg i.v. When R is phenyl orhalo-substituted phenyl, or when Alk-R is dialkoxybenzyl, administrationof about 1-16 mg/kg i.v. to an anesthetized dog elicits about a 30-40mm. Hg. rise in arterial blood pressure, indicating pressor activity. Inaddition, ganglion blocking activity is specifically observed with twotypes of compounds within formula (I-b), namely, those wherein Alk-R iseither dihalophenethyl or B-methyl-phenethyl at doses of about 10-20mg/kg i.v. in anesthetized dogs. With the formula (Ib) compounds inwhich R is lower alkoxy, lower alkyl or methylenedioxy substitutedphenyl, a decrease in the heart rate has been found upon i.v. admin- Thesubject compounds may be prepared by reacting a fluoborate of formula(II) with a primary amine (III) having the formula NI-I -Z, wherein Z isCH(C H for compounds of formula (l-a) and -Alk-R for compounds offormula (lb). Stoichiometric quantities of reactants are preferablyemployed. The starting material II may be prepared according to Ber.,89, 2063 (1956). Suitable organic solvents for conducting the reactioninclude lower aliphatic alcohols, such as, for example, methanol,ethanol, 2- propanol, tert-butanol and the like; ethers, such as, forexample diethylether, tetrahydrofuran, dioxane and the like; lowerhalogenated hydrocarbons such as chloroform, methylene chloride,1,2-dichloroethane and the like; and aromatic hydrocarbons such asbenzene, toluene, xylene and the like. Elevated temperatures may beadvantageously employed during the reaction. The resulting product (IV),in the form of the fluoborate salt, is converted to the correspondingbase form (I) by conventional means, for example, by treatment with asuitable alkali such as alkali metal or alkaline earth metal hydroxides,carbonates and the like. The reactions may be illustrated as follows:

@Mom 2 wig) \ir (III) (In). rte-OH (Iv) The preferred method of makingthe 1R 2[(hydroxyphenyl-Alk)imino]-methyleneimines of formula (l-b)consists in conventional hydrolysis of the alkoxy function in thecorresponding 1-R -2-[(lower alkoxyphenyl-Alk)imino]-methyleneimines,for example, by refluxing the latter for several hours in glacial aceticacid and hydrobromic acid. In turn, conventional O- alkylation of thehydroxy function, for example, by treatment with an appropriate loweralkyl halide alkylating agent in alcohol under reflux, provides thecorresponding 1-R -2-[(1ower alkoxypheny1-A1k)imino]- methyleneimines offormula (l-b).

Alternatively, the subject compounds of formula (l-b) may be prepared byreacting a l-R methyleneimine-Z-one lower alkyl acetal [see Annalen,641, 1 (1961) for the general method of preparing this type of startingmaterial], a l-R -2-lower alkylthiomethyleneiminium salt such as, forexample, l-lower alkyl 2-methylthiopyrrolidinium methosulfate [seeAnnalen, 651, 89 (1962) for the general method of preparing this type ofstarting material], or the phosphorous oxychloride adduct or chlorideprepared from a 1-R -methyleneimine-2-one [see Berichte, 94, 2278 (1961)and Berichte, 96, 2671 (1963) for the general method of preparing thesetypes of starting materials] with the primary amine (111) having theformula NH Z. The reactants are preferably mixed in stoichiometricamounts, either witl'i'out solvent if the amine is a liquid or with asuitable organic solvent. Elevated temperatures may be advantageouslyemployed during these reactions. The products, when obtained as salts,may be converted to the corresponding base form (I) as describedpreviously.

The subject compounds may be isolated as the free bases by syntheticprocesses normally employed. These compounds, in base form, areconvertible to therapeutically active non-toxic acid addition salts bytreatment with an appropriate acid, such as, for example, an inorganicacid, such as, hydrohalic acid, e.g., hydrochloric, hydrobromic,hydroiodic acid; sulfuric or nitric acid; a phosphoric acid; an organicacid, such as, acetic, propionic, glycolic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic,mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic,p-aminosalicylic, 2- phenoxybenzoic, or Z-acetoxybenzoic acid.Conversely, the salt form can be converted in the usual manner into thefree base.

The preferred 2-aralkylimino-1-R -piperidines of this invention may bedescribed by the following formula:

wherein n is the integer 1 or 2; R, is a member selected from the groupconsisting of loweralkyl and benzyl; and R is a member selected from thegroup consisting of phenyl, monoand di-substituted phenyl andmethylenedioxypheny], each substituent of said substituted phenyls beinga member selected from the group consisting of halo, loweralkyl,loweralkoxy and hydroxy.

The invention may be illustrated by, although not limited to thefollowing examples.

EXAMPLE I 1-Methy1-2-[(1,1-diphenylmethyl)imino]-pyrrolidine 21.5 Grams(0.1 mole) of l-methyl-Z- ethoxypyrrolidinium fluoroborate are added to18.3 grams (0.1 mole) of benzhydrylamine (exothermic reaction). Themixture is heated an additional 15 minutes on a steam cone and thencooled. Ether is added and the crystalline salt collected by filtration.The salt is suspended in water and the mixture made basic with sodiumhydroxide solution. The resulting product is extracted into methylenechloride. The extracts are washed once with water, dried over magnesiumsulfate, filtered and concentrated in vacuo. The crude crystallineproduct is slurried in petroleum ether and collected by filtration; m.p.1071 14C. Recrystallization from methylene chloride-petroleum etheraffords pure 1 -methyl-2-[(1,1-diphenylmethyl)imino]-pyrrolidine, m.p.,l12l13C.

EXAMPLE II The procedure of Example I is followed, except thatequivalent quantities of the l-ethyl and l-butyl derivatires of2-ethoxypyrrolidinium fluoroborate are respectively utilized in lieu ofthe l-methyl-Z- ethoxypyrrolidinium fluoroborate used therein to yieldas products: l-ethyl-2-[(1,l-diphenylmethyl)imino]- pyrrolidine andl-butyl-2-[(1,1-diphenylmethyl- )iminol-pyrrolidine, respectively.

EXAMPLE 111 Treatment of the l-methyl, l-ethyl and l-butyl derivativesof 2-[(1,l-diphenylmethyl)imino]-pyrrolidine obtained from Examples 1and II with mineral acids such as hydrochloric acid and hydrobromic acidafford the corresponding acid addition salts thereof.

EXAMPLE IV l-Methyl-2-benzylimino-pyrrolidine 21.4 Grams (0.2 mole) ofbenzylamine are added to about 0.15 mole l-methyl-2-ethoxypyrrolidiniumfluoborate (exothermic reaction). After the initial reaction subsides,the mixture is warmed for 1 /2 hours on a steam cone. The resulting oilyfluoborate salt is cooled and washed 3 times with ether, then dissolvedin methylene chloride, extracted twice with percent sodium hydroxide,washed with water, dried over magnesium sulfate, filtered andconcentrated in vacuo. The oily residue (32.5 g.) of crudel-methyl-2-benzyliminopyrrolidine is dissolved in acetone and treatedwith a solution of 35 grams (0.19 mole) of cyclohexanesulfamic acid inacetone. A first crop of crystals (13.9 g.) is collected by filtration.Dilution of the mother liquor, first with ether and second withpetroleum ether, affords two additional batches of crystals (34.0 g.).Recrystallization of the salt from benzene affordslmethyl-2-benzylimino-pyrrolidine cyclohexanesulfamate, m.p. 80-83C.

EXAMPLE V l-Methyl-2-phenethyliminopyrrolidine 24.2 Grams (0.2 mole) of,B-phenethylamine is added to about 0.15 molel-methyl-2-ethoxypyrrolidinium fluoborate (exothermic reaction). Afteradditional heating on a steam cone for 5 minutes, the reaction mixturecrystallizes. The mixture is cooled, slurried in ether and filtered,giving 41.4 grams of the fluoborate salt of the product. The salt isdissolved in methylene chloride and washed 3 times with dilute sodiumhydroxide and once with water, dried over magnesium sulfate, filteredand concentrated in vacuo, affording 31.0 grams of oily product, crudel-methyl-2- phenethyliminopyrrolidine. The oil is dissolved in acetoneand treated with a solution of'27.5 grams of cyclohexane-sulfamic acidin acetone. After cooling, the crystals are collected by filtration,m.p. l07llOC. Recrystallization from acetone gives 1-methyl-2-phenethyliminopyrrolidine cyclohexanesulfamate, m.p. 109l12.5C.

EXAMPLE Vl 1-Methyl-2-[(d-2-methylphenethyl )imino]pyrrolidine.

To grams (0.093 mole) of l-methyl-2- ethoxypyrrolidinium fluoborate isadded 15 grams (0.11 mole) of d-amphetamine. Crystallization beginswithin a few minutes and is allowed to continue at room temperature.Ether is added and the slurry cooled in an ice-bath. The salt crystalsare collected by filtration. The salt is dissolved in methylenechloride, extracted twice with dilute sodium hydroxide, washed withwater dried over magnesium sulfate, filtered and concentrated in vacuo.The residual oil of crude 1-methyl-2-[(d-2-methyl-phenethyl)imino]pyrrolidine is purified by columnchromatography over basic alumina (Woelm) and converted to itsperchlorate salt in percent ethanol. There is thus obtained 17.1 grams(49.5%) of pure l-methyl-2-[d-2-methylphenethyl)iminolpyrrolidineperchlorate, m.p. 129.5-l30.5C.

EXAMPLE Vll l-Methyl-2-( p-chlorobenzylimino )pyrrolidine.

To 20 grams (0.09 mole) of l-methyl-Z- ethoxypyrrolidinium fluoborate isadded 14.2 grams (0.1 mole) of p-chlorobenzylamine. After the initialreaction subsides, the mixture is heated on a steam cone for 10 minutesand then cooled. The oily product is washed 3 times with ether,dissolved in methylene chloride, washed 3 times with 10 percent sodiumhydroxide, dried over magnesium sulfate, filtered and concentrated invacuo (yield, 21.6 grams). The oily residue of crudel-methyl-2-(p-chlorobenzylimino)pyrrolidine is dissolved in acetone andtreated with 18 grams of cyclohexanesulfamic acid in acetone. Thecrystalline product is collected by filtration and recrystallized fromacetone to give 30 grams (73.5%) of l-methyl-2-(p-chlorobenzylimino)pyrrolidine cyclohexanesulfamate, m.p. 142143C.

EXAMPLE VIII The procedure of Example Vll is followed, except that anequivalent quantity of p-methylbenzylamine is utilized in lieu of thep-chlorobenzylamine used therein to yield as the respective products:1-methyl-2-(pmethylbenzylimino)pyrrolidine and the correspondingcyclohexanesulfamate salt.

EXAMPLE IX 1-Methyl-2- 3 ,4-dimethoxyphenethyl )imino pyrrolidine To 20grams of l-methyl-2-ethoxypyrrolidinium fluoroborate is added 18.1 grams(0.1 mole) of ,B-(3,4- dimethoxyphenyl)ethylamine. After the initialreaction subsides, the mixture is heated for 10 minutes on a steam cone.The mixture is cooled and the crystals are slurried in ether andcollected. The solid is slurried in water and the mixture is made basicwith 10 percent sodium hydroxide and extracted with methylene chloride.The extracts are dried over magnesium sulfate, filtered and concentratedin vacuo, yielding 30 grams of crude oilyl-methyl-2-[(3,4-dimethoxyphenethyl)imino]pyrrolidine. Columnchromatography over basic alumina affords 20 grams of material from theether eluates. Distillation of this material gives 10 grams of l-methyl-2-[(3,4-dimethoxyphenethyl)imino]pyrrolidine (b.p. l6l-,l-69C./0.35mm.), which is dissolved in acetone and treated with 7.1 grams (0.04mole) of cyclohexanesulfamic acid in acetone. When crystallization iscomplete, the material is filtered, yielding l-methyl-2- [(3,4-dimethoxyphenethyl)imino]pyrrolidine cyclohexanesulfamate, m.p. 128-l30.5C.

EXAMPLE X l-Methyl-2-[(trans-2-phenylcyclopropyl)imino]pyrrolidine To 20grams of l-methyl-2-ethoxypyrrolidinium fluo- 7 borate is added 13.3grams (0.1 mole) of trans-2- phenylcyclopropylamine (exothermicreaction). The mixture is heated for minutes on a steam cone, and, aftercooling, washed 3 times with ether. It is then dissolved in methylenechloride, washed twice with 10 percent sodium hydroxide, dried overmagnesium sulfate, filtered and concentrated in vacuo. The crudereaction product is chromatographed over basic alumina. Elution withpetroleum ether and ether yields 19.1 grams of material from the eluateswhich is then distilled to give 15.8 grams of l-methyl-2-[(trans-2-phenylcyclopropyl)imino]pyrrolidine (b.p. l43l45C./0.7 mm.). Thepurified base is dissolved in acetone and a solution of 13.2 grams (0.07mole) of cyclohexanesulfamic acid in acetone is added. The mixture iscooled and the crystals of l-methyl-2[(trans-2-phenylcyclopropyl)imino]pyrrolidine cyclohexanesulfamate arecollected on a filter, m.p. 116.5118.5C.

' EXAMPLE X1 2-[ 3 ',4'-Dimethoxyphenethyl)imino]- 1 -ethylpyrrolidineperchlorate.

Triethyloxonium fluoborate is prepared from 11.25 g. (0.08 mole) ofboron trifluoride etherate and 5.55 g. (0.06 mole) of epichlorohydrin inether. The salt is washed with ether by decantation and treated with anether solution of 6.8 g. (0.06 mole) of l-ethyl-2- pyrrolidone. Afterstirring at room temperature for 4 hours, the oily salt is washed withether by decantation, dissolved in methylene chloride and treated with asolution of 9.06 g. (0.05 mole) of B-(3,4-dimethoxyphenyl- )ethylamine.After stirring at room temperature for 17 hours, the reaction mixture iswashed with dilute sodium hydroxide, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo, yielding about g. of crudeoily 2-[(3',4'- dimethoxyphenethyl)imino]-1-ethyl-pyrrolidine which isdistilled. the desired fraction distills at 140-155C./0.25 mm. Hg. Thethus-obtained 2- [(3',4-dimethoxyphenethyl)imino]-l-ethylpyrrolidine isdissolved in ethanol and treated with an ethanolic solution of 5.25 g.of perchloric acid in ethanol. Dilution with ether yields crystals of2-[(3',4'- dimethoxyphenethylOimino]-l-ethylpyrrolidine perchlorate,which are collected by filtration, washed with ether and air-dried togive the pure perchlorate, m.p. l02-104.5C.

Analysis:

Calcd. for C l-l ,N O .HClO

C, 50.99; H, 6.69; N, 7.44; Cl, 9.41%

Found C, 51.10; H, 6.72; N, 7.41; Cl, 9.46%

EXAMPLE XII The procedure of Example X1 is repeated, except that anequivalent quantity of an appropriate-"amine, i.e., NH Z, is used inplace of the B-'(3,4-dimethoxyphenyl)ethylamine used therein to yield,as respective products, the following imino-pyrrolidines, both in baseform and as the corresponding perchlorate salt:

2-benzylimino-l-ethyl-pyrrolidine;

Z-phenethylimino-l-ethyl-pyrrolidine;

2-(p-chlorobenzyl)imino-l-ethyl-pyrrolidine; and

Z-(p-methylbenzyl)imino-l-ethyl-pyrrolidine.

EXAMPLE X111 2-[ (2 ',4-Dimethoxyphenethyl )imino l methylpyrrolidineperchlorate.

8 Triethyloxonium fluoborate is prepared from 9.45 g.

(0.0665 mole) of boron trifluoride etherate and 4.6 g.

(0.0495 mole) of epichlorohydrin. The salt is washed with ether bydecantation and treated with a solution 5 of 4.12 g. (0.0415 mole) ofl-methyl-2-pyrrolidone in ether. After stirring at room temperature for2.5 hours, the oily salt is washed with ether, dissolved in methylenechloride and treated with a solution of 7.5 g. (0.0415 mole) of2,4-dimethoxyphenethylamine in methylene chloride. After stirring atroom temperature overnight, the reaction mixture is washed with dilutesodium hydroxide, dried over anhydrous magnesium sulfate, filtered andconcentrated to dryness in vacuo giving2-[(2',4-dimethoxyphenethyl)imino]-l-methylpyrrolidine which isdissolved in ethanol and treated with a solution of 5.35 g. ofperchloric acid in ethanol. Dilution with ether and scratching affordedcrystals which are collected by filtration and-air-dried to give theperchlorate salt of 2-[(2',4'- dimethoxyphenethyl )imino]- l-methyl-pyrrolidine, m.p. l28.5-l31C. After recrystallization fromethanol, the melting point is mp. 129-132C. Analysis:

Calcd. for C|5H22N202.HC104 I C, 49.65; H, 6.39; N, 7.72; Cl, 9.77

Found C, 49,66; H, 6.41; N, 7.85; Cl, 9.64

EXAMPLE XIV 2-[(3,4-Dimethoxy-- 3O -methylphenethyl)imino]- 1-methylpyrrolidine perchlorate.

Triethyloxonium fluoborate is prepared from 5.55 g. (0.06 mole) ofepichlorohydrin and 11.25 g. (0.08 mole) of boron trifluoride etherate.The salt is washed with ether and a solution of 4.95 g. (0.05 mole) ofl-methyl-2-pyrrolidone in ether is added. After stirring at roomtemperature for 3 hours, the salt is washed with ether, dissolved inmethylene chloride and to it is added a solution of 9.75 g. (0.05 mole)of 3,4-dimethoxy-amethylphenethylamine. After stirring at roomtemperature overnight, the solution is washed with dilute sodiumhydroxide, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo giving an oily residue of crude2-[(3,4-dimethoxy-a-methylphenethyDimino]-1-methylpyrrolidine which issuspended in dilute sodium hydroxide and extracted with benzene. Theextracts are combined and dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give the oily base once againwhich is dissolved in ethanol and converted to the perchlorate salt inthe usual manner, m.p. 141-144C.

EXAMPLE XV 2-[(3 ,4 Dichlorophenethyl)imino]- 1 -methylpyrrolidinecyclohexanesulfamate.

mole) 0f ,8-(3,4-dichlorophenyl)-ethylamine is dissolved in water, madebasic with sodium hydroxide and extracted with methylene chloride. Theextracts are combined and dried over anhydrous magnesium sulfate,filtered and concentrated to about ml. and added dropwise to themethylene chloride solution of the pyrrolidinium fluoborate saltpreviously prepared. After stirring at room temperature overnight, thereaction solution is washed with dilute sodium hydroxide, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo, givingoily 2-[(3,4'- dichlorophenethyl)imino1-l-methyl-pyrrolidine which isdissolved in ether-dilute HCl and the layers separated. The ethersolution is washed with dilute HCl and the combined acid extracts arewashed with ether, made basic with sodium hydroxide and extracted withmethylene chloride. After drying and evaporating to dryness there isobtained about 12 g. of oily 2-[(-3 ,4-dichlorophenethyl)imino]-l-mcthyl-pyrrolidine which is dissolved inacetone and treated with a solution of 8.1 g. (0.045 mole) ofcyclohexylsulfamic acid in acetone. The solution is concentrated anddiluted with ether. The resulting crystals of 2-[(3,4-dichlorophenethyl)imino]-l-methyl-pyrrolidine cyclohexanesulfamate arecooled, collected by filtration and dried. After recrystallization fromacetone-ether, the m.p. is 136l41C.

EXAMPLE XVI 1-Benzyl-2-[ 3 ',4-dimethoxyphenethyl )imino]- pyrrolidinecyclohexanesulfamate.

Triethyloxonium fluoborate is prepared from 5.55 g. (0.06 mole) ofepichlorohydrin and 11.25 g. (0.08 mole) of boron trifluoride etherate.The salt is washed with ether and treated with an ether solution of 10.5g. (0.06 mole) of 1-benzyl-2-pyrrolidone and stirred at room temperaturefor three hours. The salt is washed with ether and dissolved inmethylene chloride and treated with a solution of 9.06 g. (0.05 mole) ofB-(3,4- dimethoxyphenyl)ethylamine in methylene chloride. After stirringat room temperature overnight, the reaction mixture is washed withdilute sodium hydroxide, dried and concentrated in vacuo, affording oily1- benzyl-[(3',4-dimethoxyphenethyl)imino]- pyrrolidine. After anacid-base separation, there is obtained about 16 g. of oily base whichis distilled in vacuo to give pure lbenzyl-2-[(3,4'-dimethoxy'phenethyl)imino]-pyrrolidine, b.p. l80l92C./0.2 mm. Hg., whichis dissolved in acetone and converted to its cyclohexanesulfamic salt bythe addition of 5.1 g. of cyclohexylsulfamic acid in acetone. Dilutionwith ether affords crystals of the salt which are collected byfiltration, m.p. 103108C.

EXAMPLE XVII By following the procedure of Example XVI, except that anequivalent quantity of an appropriate aralkyl amine, i.e., H N-Z", isemployed instead of the [M3,- 4-dimethoxyphenyl)-ethylamine usedtherein, the following are obtained as respective products, both as freebase and corresponding cyclohexanesulfamate salt:

l-benzyl-2-(p-chlorobenzyl)imino-pyrrolidine;

l-benzyl-2-tpmethylbenzyl)imino-pyrrolidine;l-benzyl-2'benzyliminopyrrolidine;

l-benzyl-2-[ 3 ,4-dichlorophenethyl )imino]- pyrrolidine; and

1-benzyl-2-[ (3 ,4'-methylenedioxyphenethyl- )imino]-pyrrolidine.

EXAMPLE XVIII 2-[ 3 ,4-Methylenedioxyphenethyl )imino]- 1methylpyrrolidine perchlorate.

Triethyloxonium fluoborate is prepared in ether from 5.55 g. (0.06 mole)of epichlorohydrin and 11.25 g. (0.08 mole) of boron trifluorideetherate. The salt is washed with ether by decantation and to it isadded a solution of 4.95 g. (0.05 mole) of l-methyl-2- pyrrolidone inether. After stirring for 2 hours, the salt is washed with ether bydecantation and dissolved in methylene chloride. To it is added asolution of 8.25 g. (0.05 mole) of 3,4-methylenedioxy-B-phenethylaminein methylene chloride. The reaction mixture is stirred for 2 hours atroom temperature and allowed to stand overnight. The solution is thenwashed with dilute sodium hydroxide, dried over magnesium sulfate,filtered, and concentrated to dryness in vacuo, giving oily 2([(-3,4'-methylenedioxyphenethyl)imino]l-methylpyrrolidine which isdissolved in acetone and treated with 6.75 g. of perchloric acid.Dilution with ether yields crystals of the corresponding perchloratesalt, m.p. 133-136C. Recrystallization from acetone raises the m.p. to136l40C.

EXAMPLE XIX 2-[ (p-Methoxyphenethyl )imino]- 1 -methylpyrrolidinecyclohexanesulfamate is obtained by repeating the procedure of ExampleXV. except that an equivalent amount of B-(p-methoxyphenyhethylamine isemployed in place of the dichlorophenethylamine used therein, m.p.l07112C.

EXAMPLE XX 2-[(m-Methoxyphenethyl)imino]-l-methylpyrrolidone perchlorateis obtained by following the procedure of Example XI, except that anequivalent amount of l-methyl2-pyrrolidone is used in place of1-ethy1-2-pyrrolidone and an equivalent amount of,B-m-methoxyphenethylamine is used in place of thedimethoxyphenethylamine used therein, m.p. 101l03C. (free base distillsat 130-135C./0.3mm. Hg).

EXAMPLE XXI 2-[ 3 ,4-Dimethoxybenzyl)imino]- 1 methylpyrrolidineperchlorate hemihydrate.

A solution of 5.55 g. (0.06 mole) of epichlorohydrin in ether is addeddropwise with stirring to a solution of 11.25 g. (0.08 mole) of borontrifluoride etherate in ether. After stirring for 2 hours, the oily saltis washed with ether by decantation, dissolved in methylene chloride andtreated with a solution of 4.95 g. (0.05 mole) of l-methyl-2-pyrrolidonein methylene chloride. After stirring for 2 hours, a solution of 8.36 g.(0.05 mole) of veratrylamine in methylene chloride is added. Afterstirring at room temperature overnight, the solution is washed withdilute sodium hydroxide, dried over magnesium sulfate, filtered andconcentrated to dryness in vacuo. affording the crude oily base,2-[(3,4- dimethoxybenzyl)imino]-l-methyl-pyrrolidine. An acid-baseseparation affords the oily base which is distilled at l4ll45C./0.l0.05mm. Hg. A solution of the latter in ethanol is treated with a solutionof 3,86 g. of perchloric acid in ethanol. Cooling and scratching yieldscrystals of 2-[(3',4'- dimethoxybenzyl)imino]-l-methylpyrrolidineperchlorate hemihydrate which are collected and recrystallized fromethanol (charcoaled), m.p. 1'35-138C.

EXAMPLE xxu 2-[ (3 ',4'-Dimethoxyphenethyl)imino]- l methylpiperidineperchlorate.

Triethyloxonium fluoborate is prepared in ether from 11.25 g. (0.8 mole)of boron trifluoride etherate and 5.55 g. (0.06 mole) ofepichlorohydrin. The salt is washed with ether by decantation andtreated with an ether solution of 5.65 g. (0.05 mole) of l-methyl-Z-piperidone in ether. After stirring for 3 hours, the prperidiniumfluoborate is washed with ether, dissolved in methylene chloride andtreated with a solution of 9.06 g. (0.05 mole) ofB-(3,4-dimethoxyphenethyl)amine in methylene chloride. After stirring atroom temperature overnight, the reaction solution is washed with dilutesodium hydroxide, dried over magnesium sulfate,

filtered and concentrated in vacuo, yielding crude oily 2-[ (3 ,4-dimethoxyphenethyl)imino]- 1 -methylpiperidine. An acid-base separationaffords the pure oily 2-[ 3 ',4-dimethoxyphenethyl)iminoll-methylpiperidine. An ethanol solution of 4.5 g. (0.0445 mole)of 70% perchloric acid is added to the oily base in etha- 'nol. Coolingand scratching affords crystals of the corresponding perchlorate saltwhich are collected by filtration, washed with ethanol and ether andair-dried, m.p. 135138C. Recrystallization from ethanol raises the m.p.to l3914lC.

EXAMPLE XXIII EXAMPLE XXIV 2-[ 3 ,4-Dimethoxyphenethyl)imino]-hexahydrolmethyl-ZI-I-azepine perchlorate.

Triethyloxonium fluoborate is prepared from 5.55 g. (0.06 mole) ofepichlorohydrin and 11.25 g. (0.08 mole) of boron trifluoride etheratein ether. The salt is washed with ether by decantation and treated witha solution of 7.65 g. (0.06 mole) of N- methylcaprolactam in ether.After stirring at room temperature for 3 hours, the crystalline salt iswashed with ether by decantation, dissolved in methylene chloride andtreated with a methylene chloride solution of 9.06 g. (0.05 mole) ofB-(3,4-dimethoxyphenyl)- ethylamine. After stirring at room temperatureovernight, the reaction mixture is washed with dilute sodium hydroxide,dried and concentrated in vacuo, giving crude oily2-[(3,4-dimethoxyphenethyl)imino]- hexahydro-l-methyl-ZI-I-azepine. Anacid-base separation affords the base which is distilled off (b.p.l80-185C./0.5 mm. Hg). An acetone solution of the latter and an acetonesolution of cyclohexane-sulfamic acid are mixed together. Thecyclohexanesulfamate salt of any residual phenethylamine precipitatesand is removed. The mother liquor is concentrated and treated withsufficient 50% aqueous sodium hydroxide to convert thecyclohexanesulfamate salt back to the free base, which is extracted intomethylene chloride. The methylene chloride solution is dried overanhydrous magnesium sulfate and then concentrated in vacuo. The residualoily base is then treated with an equivalent amount of perchloric acidin ethanol in the usual manner to yield the desired 2-[(3,4-dimethoxyphenethyl)imino]-hexahydrol -methyl-2H- azepine perchlorate ascrystals, m.p. l26130C. Recrystallization from ethanol raises the m.p.to l30-135C.

EXAMPLE xxv By repeating the procedure of Example XXIV, except that anequivalent amount of an appropriate amine (H H-Z) and an equivalentamount of an appropriate N-alkyl or N-benzyl hexahydro-ZH-azepine- 2-oneis used in place of N-methylcaprolactam, the following are obtained asrespective products in the form of a perchlorate salt:

2-(p-fluorobenzyl)imino-l-ethyl-hexahydro-2H- azepine;

2-[(B-4'-bromophenethyl)imino]-l-benzyl-hexahydro-2H-azepine;

2-[(B-4-methylphenethyl)imino]-l-n-butyl-hexahydro-2H-azepine; and

2-[(,B-3',4-methylenedioxy-phenethyl)imino]-lethyl-hexahydro-2H-azepine.

EXAMPLE XXVI 2-[ 3,4-Dimethoxyphenethyl)imino]- 1 -nbutylpyrrolidinecyclohexanesulfamate.

l-n-Butyl-Z-pyrrolidone (14.12 g., 0.1 mole) is dissolved in 25 ml. ofbenzene and cooled in a water bath. To this solution is added, withstirring 15.2 g. (0.1 mole) of phosphorous oxychloride and afterrefluxing for 10 minutes, the reaction mixture is cooled to roomtemperature. A solution of 18.12 g. (0.] mole) of8-3,4-dimethoxy-phenethylamine in 25 ml. of benzene is added dropwisewith stirring to the above solution (water bath cooling continued). Aslurry forms but dissolves with heating. The reaction mixture isrefluxed for 2 hours; cooled to room temperature and poured onto 100 ml.of water containing 4.0 g. (0.1 mole) of NaOI-I. The resulting gel isextracted with benzene (4 X 100 ml.). The extracts are combined anddried over anhydrous MgSO, and evaporated in vacuo leaving an oilyresidue. After acid-base purification, the product is extracted intoether (4 X 100 ml.). The combined extracts are dried over anydrous MgSOand evaporated in vacuo leaving an oily residue which is dissolved inacetone. An equivalent amount of cyclohexylsulfamic acid dissolved inacetone is added. Cooling and scratching affords the crude product,2-[(3,4'- dimethoxyphenethyl )imino]- 1 -n-butylpyrrolidinecyclohexanesulfamate, m.p. 92-95.5C. Recrystallization from acetonegives the pure product, m.p. 9597C.

EXAMPLE XXVII 2-[ 3,4'-Diethoxyphenethyl )imino]- 1 methylpyrrolidinecyclohexanesulfamate.

To 0.06mole of triethyloxonium fluoborate [pre- 13 pared by the methodof Meerwein et al., Ann., 641, 1 (1961)]in ether is added 5.95 g. (0.06mole) of l-methyl-Z-pyrrolidone in 30 ml. of dry other. After stirringunder dry nitrogen for 3 hours at room temperature, the resulting oil iswashed by decantation (4 X 50.75 ml. of dry ether), dissolved inmethylene chloride and treated with 10.46 g. (0.05 mole) ofB-3,4-diethoxyphenethylamine in 30 ml. of methylene chloride. Thereaction mixture is stirred overnight at room temperature under anatmosphere of dry nitrogen. The reaction mixture is washed with diluteNaOh (10%) (2 X 75 ml.). Extraction of the product into dilute HCl (10%)followed by basification with excess NaOh (50%) and ether extractiongives after drying (MgSO and solvent removal in vacuo, about 9.5 g. ofoily 2-[(3',4'- diethoxyphenethyl)imino]-l-methylpyrrolidine. An acetonesolution of the oil is treated with 5.9 g. (0.0327 mole) ofcyclohexanesulfamic acid in acetone. Cooling and scratching gives thecrude salt, 2-[(3,4- diethoxyphenethyl)imino]-1-methylpyrrolidinecyclohexanesulfamate. Recrystallization from acetoneether and acetoneaffords the pure salt; m.p. 94.5-96.5C.

EXAMPLE XXVIII 2-[(3',4'-Diethoxyphenethyl)imino]-1- methylpyrrolidinecyclohexanesulfamate may be also prepared by refluxing 3.15 g. (0.01mole) of the product of Example XXIX with 4.68 g. (0.03 mole) of ethyliodide while adding dropwise 6 ml. (0.03 mole) of aqueous N NaOH. Afterthe addition is complete, refluxing is continued for 2 hours.Conventional workup and the conversion to the cyclohexanesulfamate saltgives the desired product.

EXAMLPE XXIX 2-[ 3 ,4-Dihydroxyphenethyl)imino]- 1 methylpyrrolidinehydrobromide.

Five Grams (0.013 mole) of oily 2-[(3,4'-dimethoxyphenethyl)imino]-l-methyl-2pyrrolidone is dissolved inmethylene chloride, cooled to -70C. and treated with a methylenechloride solution of 2.8 g. (0.013 mole) of boron tribromide. Thereaction is then allowed to warm to room temperature and stirred for 4hours (total). The solution is concentrated in vacuo; the residue isdissolved in methanol, concentrated in vacuo, dissolved in water andconcentrated in vacuo. The addition of methanol and ether affordscrystals of 2-[(3',4'-dihydrophenethyl)imino]-1- methylpyrrolidinehydrobromide which are recrystallized from methanol ether to give theproduct as an offwhite solid.

EXAMPLE XXX 2-[ 3 ',4'-Dihydroxypnenethyl)imino]- 1 methylpyrrolidine.

A solution of 34.35 g. (0.09 mole) of 2-[(3,4'-dimethoxyphenethyl)imino]-l-methylpyrrolidine is refluxed with 68.7 ml.of 48% l-lBr and 68.7 ml. of glacial acetic acid for 22 hours. Coolingto room temperature affords an impure crop which is removed byfiltration. Cooling of the mother liquor in an ice bath affords 2-[(3',4'-dihydroxyphenethyl)imino]-lmethylpyrrolidine as crystals, m.p.215216.5C.

14 EXAMLPE XXXl 1-Methyl-2-[(3,4-dimethoxyphenethyl)imino]- pyrrolidinemay be also prepared by refluxing an ethanolic solution of2-[(3,4'-dihydroxyphenethyl)imino1- 5 l-methylpyrrolidine with twoequivalents of methyl iodide while adding dropwise an aqueous solutionof sodium hydroxide (3 equivalents). Conventional acidbase extractionand conversion to the cyclohexanesulfamate salt gives the desiredproduct.

EXAMPLE XXXll By repeating the procedure of Example XXIX, except that anequivalent quantity of the 3,4-dimethoxyand p-methoxy-phenethyliminopiperidines (converted to base form) obtained from Examples XXll andXXlll.

respectively. are utilized as starting materials, the following productsare obtained:

2-[(3,4'-dihydroxyphenethyl)imino]-lmethylpiperidine; and

2-[(p-hydroxyphenethyl)imino]-l-methylpiperidine.

EXAMPLE XXXlll the formula:

and the therapeutically active acid addition salts thereof, wherein n isthe integer 1 or 2; R is a member selected from the group consisting ofloweralkyl and benzyl; and R is a member selected from the groupconsisting of phenyl, monoand di-substituted phenyl andmethylenedioxyphenyl, each substituent of said substituted phenyls beinga member selected from the group consisting of halo, loweralkyl,loweralkoxy and hydroxy.

2. 2-[(Diloweralkoxyphenethyl)imino]-lloweralkylpiperidine.

methylpiperidine.

3. 2-[ 3',4-Dimethoxyphenethyl)imino} 1 UNITED STATES PATENT ANDTRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,887,569 Page 1of 2 DATED 2 June 3,1975 INVENTORG) 1 George Ireland Poos It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

In Column 5, line 5, "diphenylmethyl" should read diphenylmethyl) InColumn 5, line 53, "cyclohexane-sulfamic" should readcyclohexenesulfamic In Column 8, line 26, "C, r9,66" should read C, #966t In Column 8, line 29, "Dimethoxy" should read mmethoX -d In Column 8,line 65, "Of" should read of In Column 9, line 62,"methylenedioxyphenethyl-" should read methylenedioxyphenethyl) InColumn 9, line 63, ")imino] should read imin5 1--.

In Column 10, line 1 "2([(". should read 2-[(3' In Column 10, line 58,delete the period after "in vacuo" and insert a come (a) In Cilumn 10,line 62, "3,86" should read 3.86

'[SEAL] UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OFCORRECTIQN PATENT NO. 3387569 DATED June- 1975 INV ENTOR(S) GeorgeIreland Poms Page 2 o 2 It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Line 65. (under Eixamme XXX), D'ihydroxynheneihvl-.

In 'lohmn 1 5, 29.. erflt; should b self:

Signed and Scaled this ninth Day of December 1975 A ttest:

RUTHC. MASON Commissioner ofPatenrs and Trademarks DihvdroxypnemetkwUNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. I 3 887 569 DATED June 3, 975

INVENTOR( 1 George Ireland Poos it is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

In Column 7, line k7, "dinethoxyphenethylOimino" should read amthoxheneth nmn 'In Column 11, line 11, "prperidiniul" should readpiperidinim Signed and Sealed this sixth D y of January 1976 [SEAL]Attest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner oj'Parenrsand Trademarks

1. A chemical compound selected from the group consisting of a2-aralkylimino-1-R1-piperidine having the formula:
 1. A CHEMICALCOMPOUND SELECTED FROM THE GROUP CONSISTING OF A2-ARALKYLIMINO-1-R1-PIPERIDINE HAVING THE FORMULA: 2.2-((Diloweralkoxyphenethyl)imino)-1-loweralkylpiperidine.